Severe Symptomatic Infection Research Articles

Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance.

Enterovirus-D68 (EV68) has emerged as a global health concern over the last decade with severe symptomatic infections resulting in long-lasting neurological deficits and death. Unfortunately, there are currently no FDA-approved antiviral drugs for EV68 or any other non-polio enterovirus. One particularly attractive class of potential drugs are small molecules inhibitors, which can target the conserved active site of EV68-3C protease. For other viral proteases, we have demonstrated that the emergence of drug resistance can be minimized by designing inhibitors that leverage the evolutionary constraints of substrate specificity. However, the structural characterization of EV68-3C protease bound to its substrates has been lacking. Here, we have determined the substrate specificity of EV68-3C protease through molecular modeling, molecular dynamics (MD) simulations, and co-crystal structures. Molecular models enabled us to successfully characterize the conserved hydrogen-bond networks between EV68-3C protease and the peptides corresponding to the viral cleavage sites. In addition, co-crystal structures we determined have revealed substrate-induced conformational changes of the protease which involved new interactions, primarily surrounding the S1 pocket. We calculated the substrate envelope, the three-dimensional consensus volume occupied by the substrates within the active site. With the elucidation of the EV68-3C protease substrate envelope, we evaluated how 3C protease inhibitors, AG7088 and SG-85, fit within the active site to predict potential resistance mutations.

Contribution of fetal blood sampling to determining the prognosis of congenital cytomegalovirus infections: a case-cohort study in Switzerland

Cytomegalovirus is responsible for the most common congenital infection, affecting 0.5% to 1.0% of live births in Europe. Congenital cytomegalovirus infection can be diagnosed during pregnancy by viral DNA amplification in the amniotic fluid, but the prognosis of fetuses without severe brain abnormalities remains difficult to establish on the basis of prenatal imaging alone. To identify predictors of moderate to severe symptomatic cytomegalovirus infection among fetal blood parameters and to propose an algorithm on the basis of these parameters and on prenatal imaging that would provide the best positive and negative predictive values. Fetal blood sampling at 21-28 weeks gestation was performed in fetuses with congenital cytomegalovirus infection confirmed by amniocentesis after maternal infection in the first-trimester or periconceptional period. We compared the levels of hemoglobin, thrombocytes, γ-glutamyl transpeptidase, aspartate aminotransferase, alanine aminotransferase, β2-microglobulin, immunoglobulins G and M, and cytomegalovirus DNA viral loads in amniotic fluid and fetal blood between those with moderate to severe symptomatic infection and those with asymptomatic to mild infection (median follow-up of 36 months for live births). Among 58 fetuses included, 25 (43%) had a moderate to severe symptomatic infection: 16 with severe cerebral abnormalities, 5 with multiple signs or symptoms at birth, 2 with bilateral sensorineural hearing loss, and 2 with neurodevelopmental delay. The values of thrombocytes, aspartate aminotransferase, β2 microglobulin, Immunoglobulin M, and cytomegalovirus viral loads differed significantly between fetuses with moderate to severe symptomatic infection and those with asymptomatic to mild infection. The optimal strategy to predict moderate to severe symptomatic infection was to first perform fetal brain imaging, followed by fetal blood sampling with the following cutoffs: thrombocytes <120,000/mL, viremia ≥5 log10/mL, and β2 microglobulin ≥12 mg/L). This recursive algorithm had a negative predictive value of 100% for moderately to severely symptomatic infection. The combination of thrombocytes, β2-microglobulin, and cytomegalovirus viral load in fetal blood can be used for prognosis determination, particularly in cytomegalovirus-infected fetuses without severe brain abnormalities at the time of prenatal diagnosis. Future studies should evaluate whether these parameters remain useful in infected fetuses who have been treated with valacyclovir before fetal blood sampling.

Insights for COVID-19 in 2023.

Predictions for a near end of the pandemic by the World Health Organization should be interpreted with caution. Current evidence indicates that the efficacy of a fourth dose of classical mRNA vaccines (BT162b2 or mRNA-1273) is low and short-lived in preventing SARS-CoV-2 infection in its predominant variant (Omicron). However, its efficacy is high against severe symptomatic infection, hospitalization and death. The new vaccines being introduced are bivalent and active against the Omicron variants. Potential new vaccines to be introduced in the coming year include a vaccine based on a recombinant protein that emulates the receptor binding domain of the Spike protein under development by the Spanish company Hipra, as well as vaccines for nasal or oral administration. Available information suggests that vaccines against COVID-19 can be administered in association with influenza vaccination without particular complications. New drugs against COVID-19, both antiviral and anti-inflammatory, are under investigation, but this does not seem to be the case with monoclonal antibodies. The indication to use masks in some circumstances will be maintained next year in view of the accumulation of scientific data on their efficacy. Finally, the long COVID or Post-COVID syndrome may continue to affect a very high proportion of patients who have had the disease, requiring combined diagnostic and therapeutic resources.

Multisystem inflammatory syndrome in children: A unique manifestation of COVID-19

During the coronavirus disease 2019 (COVID-19) pandemic, children have been relatively spared from the severe symptomatic infection affecting adults, particularly the elderly and those with comorbidities. One of the most challenging aspects of paediatric SARS-CoV-2 infection has been the discovery of a unique late manifestation of infection characterised by fever, systemic inflammation and multiorgan involvement.

Characterizing the COVID-19 Illness Experience to Inform the Study of Post-acute Sequelae and Recovery.

BackgroundThere is an urgent need to fully understand the impact of variable COVID-19 experiences and the optimal management of post-acute sequelae of SARS-CoV-2 infection. We characterized the variability in the acute illness experience and ongoing recovery process from participants in a COVID-19 recovery cohort study in Northern California in 2020.MethodWe completed 24 semi-structured in-depth interviews with adults with confirmed positive SARV-CoV-2 nucleic acid amplification test result, had recovered or were recovering from acute infection, and underwent serial evaluations. We purposefully sampled English- and Spanish-speaking adults with asymptomatic, mild, and severe symptomatic infection, including those who were hospitalized and those with HIV co-infection. We used a thematic analysis to analyze interviews and identify salient themes.ResultsAfter integrating the thematic analysis with clinical data, we identified key themes: (1) across symptom profiles and severity, experiencing COVID-19 was associated with psychological distress; (2) symptomatic infection carried uncertainty in symptom presentation and ongoing recovery (e.g., long COVID); and (3) health information-seeking behavior was facilitated by access to medical care and uncertainty with the recovery process.ConclusionOur data informs the emerging field of “long COVID” research and shows a need to provide information and continuous support to persons with post-acute sequelae to ensure they feel secure along the path to recovery.

Effectiveness of BNT162b2 COVID-19 Vaccine in Preventing Severe Symptomatic Infection among Healthcare Workers.

Background and Objectives: This study aims to evaluate the effectiveness of the BNT162b2 COVID-19 (coronavirus disease 2019) in preventing severe symptomatic laboratory-confirmed infection among healthcare workers in a real-world scenario. Materials and Methods: A cross-sectional analysis of a prospective cohort study was conducted. Subjects with onset illness from January to February 2021 were eligible and classified according to the number of vaccine doses received (single-shot, n = 8; two-shot, n = 12; unvaccinated, n = 290). Results: The vaccine effectiveness against severe illness was 100% in the single and two-shot group. The presented results suggest that vaccination reduces the frequency of severe symptomatic COVID-19 in working-age adults. Conclusions: Efforts focusing on maximizing the number of immunized subjects in the study population may reduce associated economic and social burdens.

Parvovirus Encephalitis: Looking Through the Eyes

Parvovirus B19 usually causes less severe symptomatic infections. Its severity depends upon the affected cells of a particular organ system. Whereas diseases affecting the skin and haematological systems tend to be milder, affection of CNS may turn serious. Direct invasion or NS1 toxicity of Parvo virus B19 has been postulated behind CNS tropism. Here we depict Parvovirus B19 causing acute encephalitis and ophthalmoplegia in an immunocompetent male child, taking an eventful course, responded with IVIG &amp; steroids, reversed the symptoms except some VEP abnormalities. This explores the need for timely intervention with immunotherapy in such cases to prevent permanent sequelae.

Identification of new viral variants specific to the honey bee mite Varroa destructor.

Large-scale colony losses among managed Western honey bees have become a serious threat to the beekeeping industry in the last decade. Multiple factors contribute to these losses, but the impact of Varroa destructor parasitism is by far the most important, along with the contribution of some pathogenic viruses vectored by the mite. So far, more than 20 viruses have been identified infecting the honey bee, most of them RNA viruses. They may be maintained either as covert infections or causing severe symptomatic infections, compromising the viability of the colony. In silico analysis of available transcriptomic data obtained from mites collected in the USA and Europe, as well as additional investigation with new samples collected locally, allowed the description of three RNA viruses, two of them variants of the previously described VDV-2 and VDV-3 and the other a new species reported here for the first time. Our results showed that these viruses were widespread among samples and that they were present in the mites as well as in the bees but with differences in the relative abundance and prevalence. However, we have obtained strong evidence showing that these three viruses were able to replicate in the mite, but not in the bee, suggesting that they are selectively infecting the mite. This opens the door to future applications that may help controlling the mite through biological control approaches.

Clostridium difficile infection in the postcolectomy patient.

Clostridium difficile infection (CDI) after total colectomy has been increasingly recognized over the past decade. C. difficile enteritis (CDE) is a rare occurrence, whereas C. difficile pouchitis (CDP) has been reported in approximately 10% of symptomatic patients seen at a referral center for pouch dysfunction. Similar to colonic CDI in the general population, antibiotic use and comorbid diseases may be risk factors for CDE. In contrast, the postoperative use of antibiotics does not seem to be associated with CDP, whereas male gender, recent hospitalization, and presurgery antibiotic use were shown to be risk factors for CDP. C. difficile is capable of colonizing all intestinal sites, including the ileal pouch. Similarities with the colon at physiological and cellular levels may contribute to the susceptibility of the ileal pouch to CDI. Postcolectomy CDI likely represents a disease spectrum from asymptomatic colonization to severe symptomatic infection. CDI should be considered in ostomy patients with fever and increased ileostomy output and in ileal pouch patients with a change in "normal" symptom pattern or chronic antibiotic-refractory pouchitis. Sensitive and specific methods for detection of CDI are available, and endoscopy is useful in evaluating the patient with suspected CDE or CDP, although pseudomembranes are typically absent. Vancomycin is used as the first-line therapy for CDP and may be warranted for patients with inflammatory bowel disease with CDE. Fecal microbiota transplantation has found its use in the management of severe or antibiotic refractory CDP, but this approach requires evaluation for the management of refractory CDE.

Clostridium difficile infection in patients with ileal pouches.

Clostridium difficile (C. difficile) infection (CDI) following total proctocolectomy and ileal pouch-anal anastomosis has been increasingly recognized over the past 5 years. CDI of the ileal pouch has been recognized in ∼10% of symptomatic patients seen at a tertiary referral center for pouch dysfunction. In contrast to colonic CDI in the general population or in patients with inflammatory bowel disease, postoperative antibiotic exposure and the use of immunosuppressive agents or proton pump inhibitors do not appear to be associated with CDI of the pouch. Male gender, recent hospitalization, and presurgery antibiotic use were shown to be risk factors for ileal pouch CDI. The ileal pouch may be susceptible to CDI owing to similarities with the colon at physiological and structural levels. Postcolectomy CDI likely represents a spectrum of disease processes, varying from asymptomatic colonization to severe symptomatic infection. CDI should be considered in any patient with an ileal pouch presenting with a change in "normal" symptom pattern or treatment-refractory disease. Sensitive and specific methods for the detection of CDI are available, and pouchoscopy is a valuable tool in the evaluation of the patient with symptomatic CDI of the pouch. At a referral center for pouch dysfunction, vancomycin is used as the first-line therapy for ileal pouch CDI. Fecal microbiota transplantation may find use in the management of severe or antibiotic refractory CDI-related pouchitis.